Garbrecht, U.S. Pat. No. 3,580,916, discloses a group of lysergic (I) and 9,10-dihydrolysergic acid (II) esters formed with various open chain and cyclic diols. The following structures summarize the disclosure in Garbrecht. ##STR1## wherein R.sup.1 is H, C.sub.1-3 alkyl, allyl or benzyl and R.sup.2 is C.sub.2 -C.sub.8 monohydroxyalkyl, C.sub.2-8 dihydroxyalkyl or C.sub.5-11 monohydroxycycloalkyl having from 5-8 ring carbons. The compounds are useful as serotonin antagonists, the patent stating that "In animals, the compounds act as neurosedatives . . . and are therefor useful in calming . . . animals". The use of compounds according to II, wherein R.sup.2 is mono or dihydroxyalkyl, in migraine and other disease states characterized by an excess of peripheral 5HT, is disclosed in EPO No. 122,044 published 10-17-84.
The interest in the Garbrecht compounds has been intensified by the finding that they had excellent peripheral serotonin antagonist activity against 5HT.sub.2 receptors and did not interact, either as agonists or antagonists, with other receptors, particularly alpha.sub.1 receptors.
The most active peripheral serotonin antagonist from Garbrecht was the compound 1-isopropyl-6-methyl-8.beta.-(1-methyl-2-hydroxy)propoxycarbonyl-5R-ergoli ne (II in which R.sup.1 is isopropyl and R.sup.2 is 1-methyl-2-hydroxypropyl). In the above name, 5R refers to the beta orientation of the C-5 hydrogen. The C-10 hydrogen is alpha--10R, and the beta orientation at C-8 is the same as in either lysergic or 9,10-dihydrolysergic acid--8R. Both of these acids have a 6-methyl group. An alternate name for the Garbrecht compound is 1-isopropyl-9,10-dihydrolysergic acid 1-methyl-2-hydroxypropyl ester. Cohen et al. J.P.E.T., 227, 327 (1983) (Cohen I) reported that the above compound, given the code number LY53857, was a potent antagonist of vascular contraction to serotonin, which effect is mediated by 5HT.sub.2 receptors. The compound had minimal affinity for vascular alpha adrenergic, dopaminergic and histaminergic receptors (K.sub.dissoc. .congruent.10.sup.-10 vs .congruent.10.sup.-5). Other papers on the pharmacology of LY53857 include Cohen et al., J.P.E.T., 232, 770 (1985) (Cohen III), Harriet Lemberger et al., Life Sciences, 35, 71 (1984), Cohen, Drug Development Res., 5, 313 (1985), (Cohen IV). Cohen and Fuller, EPO No. 122,044 published 10-17-84, covers the use of hydroxyalkyl esters of 1-alkyl 9,10-dihydrolysergic acid as peripheral 5HT.sub.2 receptor antagonists.
Four additional examples of ergolines with a substituent on the indole nitrogen are: U.S. Pat. No. 3,113,133, Hofmann et al., which discloses and claims esters and amides carrying an indole N substituent such as a lower alkyl or alkenyl group or an aralkyl group. The compounds are said to be useful as serotonin antagonists, in treating inflammatory, arthritic and allergic diseases and in treating carcinoid syndrome.
U.S. Pat. No. 3,249,617, Hofmann et al., which covers (indole) N-alkyl or allyl lysergic acids, useful as intermediates.
U.S. Pat. No. 3,228,941, Bernardi et al., which discloses and claims a group of (indole) N-methylergolines--amides, hydroxamides and amidines. The compounds are alleged to have oxytoxic, adrenolytic, hypotensive, sedative and antienteraminic action.
U.S. Pat. No. 4,230,859 to Rucman which discloses dihydrolysergic acid carrying various C.sub.1-5 alkyl groups on the indole nitrogen. The compounds are said to be useful intermediates.
Finally, ergolines actually used in the treatment of migraine include the amides: ergotamine, methysergide and ergonovine.
None of the above references indicate that cyclic ether esters of an N-alkylated dihydrolysergic acid would have peripheral serotonin antagonist properties.